rs532625

chr13-110211878-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001845.6(COL4A1):c.432T>A(p.Ala144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 1,613,492 control chromosomes in the GnomAD database, including 180,476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14787 hom., cov: 31)
  • Exomes 𝑓: 0.47 (165689 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0960

Genes affected

COL4A1 (HGNC:2202): (collagen type IV alpha 1 chain) This gene encodes a type IV collagen alpha protein. Type IV collagen proteins are integral components of basement membranes. This gene shares a bidirectional promoter with a paralogous gene on the opposite strand. The protein consists of an amino-terminal 7S domain, a triple-helix forming collagenous domain, and a carboxy-terminal non-collagenous domain. It functions as part of a heterotrimer and interacts with other extracellular matrix components such as perlecans, proteoglycans, and laminins. In addition, proteolytic cleavage of the non-collagenous carboxy-terminal domain results in a biologically active fragment known as arresten, which has anti-angiogenic and tumor suppressor properties. Mutations in this gene cause porencephaly, cerebrovascular disease, and renal and muscular defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 13-110211878-A-T is Benign according to our data. Variant chr13-110211878-A-T is described in ClinVar as [Benign]. Clinvar id is 258254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110211878-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.096 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.432T>A	p.Ala144=	synonymous_variant	7/52	ENST00000375820.10
COL4A1	NM_001303110.2	c.432T>A	p.Ala144=	synonymous_variant	7/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.432T>A	p.Ala144=	synonymous_variant	7/52	1	NM_001845.6	P1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66384 AN: 151860 Hom.: 14785 Cov.: 31

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.475

GnomAD3 exomes AF: 0.467 AC: 117374 AN: 251402 Hom.: 28211 AF XY: 0.476 AC XY: 64756 AN XY: 135906

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.528

Gnomad EAS exome AF: 0.496

Gnomad SAS exome AF: 0.591

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.466

Gnomad OTH exome AF: 0.480

GnomAD4 exome AF: 0.474 AC: 692386 AN: 1461514 Hom.: 165689 Cov.: 47 AF XY: 0.478 AC XY: 347442 AN XY: 727068

Gnomad4 AFR exome AF: 0.359

Gnomad4 AMR exome AF: 0.401

Gnomad4 ASJ exome AF: 0.530

Gnomad4 EAS exome AF: 0.544

Gnomad4 SAS exome AF: 0.584

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.470

Gnomad4 OTH exome AF: 0.481

GnomAD4 genome AF: 0.437 AC: 66399 AN: 151978 Hom.: 14787 Cov.: 31 AF XY: 0.437 AC XY: 32450 AN XY: 74280

Gnomad4 AFR AF: 0.371

Gnomad4 AMR AF: 0.416

Gnomad4 ASJ AF: 0.517

Gnomad4 EAS AF: 0.516

Gnomad4 SAS AF: 0.595

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.464

Gnomad4 OTH AF: 0.472

Alfa AF: 0.463 Hom.: 5463

Bravo AF: 0.433

Asia WGS AF: 0.542 AC: 1884 AN: 3478

EpiCase AF: 0.481

EpiControl AF: 0.482

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Brain small vessel disease 1 with or without ocular anomalies Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Porencephalic cyst Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.34
Dann	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs532625; hg19: chr13-110864225; COSMIC: COSV65425800;